The impact of air pollution on cardiopulmonary health is well documented. Recently, a number of epidemiological studies have reported a potential role for vehicular sources of air pollution as a major contributor to cardiovascular disease. Unfortunately, there is a lack of comprehensive human cardiovascular toxicity information for fresh vehicle emissions from which to establish causality, identify vulnerable individuals, and refine protective regulations. In the Parent R01, we have observed that freshly generated particulate matter may have a greater physical association with volatile and semi-volatile organic species, and that such particles may be more toxic to the cardiovascular system. The implications of this phenomenon may mean public health outcomes might not simply be determined by high levels of emissions, but also by proximity to the origins of those components. This ViCTER Proposal aims to expand the Parent R01 grant in two directions, namely using human exposure studies and examining the potential role for dysfunctional high-density lipoprotein to mediate systemic cardiovascular health effects. In Project 1, with Drs. Armijos and Olvera at UTEP, we will conduct a real-world exposure scenario to test the gas-particle interaction concept in human subjects. In Project 2, with Dr. Araujo at UCLA, we will expand beyond proteomic exploration of the serum and study lipids and lipoprotein modifications, and the resultant bioactivity changes caused by exposures, both in the ongoing rodent studies, and also with the proposed human exposures. Lastly, in Project 3, with Dr. Campen at UNM, we will explore the endothelial inflammatory potential of serum from the exposed humans, which will provide a crucial pathophysiological link between the real-world exposures in Project 1 and the HDL modifications and lipid peroxidation assessed in Project 2. Collectively, these Projects will test our hypothesis that VOC-rich PM will be more toxic than the carbon core of traffic-derived PM, in terms of driving circulating inflammatory potential and HDL dysfunction. This grant will incorporate the expertise of four investigators with complementary expertise and focused interest in Border Environmental Health, Drs. Araujo, Armijos, Campen, and Olvera. Outcomes will bridge ongoing toxicological and translational work being conducted among the groups. Study results will help identify regional PM/gas contrasts and airshed compositions that may be specifically deleterious to human health. Additionally we will characterize the pathophysiological role for modified HDL in mediating the systemic vascular effects of inhaled pollutants, which will provide vital information on vulnerability of specific subpopulations.